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The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.
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Neoplasias Encefálicas , Glioblastoma , Proteogenômica , Animais , Humanos , Glioblastoma/genética , Proteínas Proto-Oncogênicas B-raf , Proteômica , Linhagem Celular Tumoral , Recidiva Local de Neoplasia , Modelos Animais de Doenças , Neoplasias Encefálicas/genética , Resistencia a Medicamentos Antineoplásicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma is the most common type of malignant primary brain tumor and displays highly aggressive and heterogeneous phenotypes. The transcription factor STAT3 has been reported to play a key role in glioblastoma malignancy. Thus, discovering targets and functional downstream networks regulated by STAT3 that govern glioblastoma pathogenesis may lead to improved treatment strategies. In this study, we identified that poly(A)-specific ribonuclease (PARN), a key modulator of RNA metabolism, activates EGFR-STAT3 signaling to support glioblastoma stem cells (GSC). Functional integrative analysis of STAT3 found PARN as the top-scoring transcriptional target involved in RNA processing in patients with glioblastoma, and PARN expression was strongly correlated with poor patient survival and elevated malignancy. PARN positively regulated self-renewal and proliferation of GSCs through its 3'-5' exoribonuclease activity. EGFR was identified as a clinically relevant target of PARN in GSCs. PARN positively modulated EGFR by negatively regulating the EGFR-targeting miRNA miR-7, and increased EGFR expression created a positive feedback loop to increase STAT3 activation. PARN depletion in GSCs reduced infiltration and prolonged survival in orthotopic brain tumor xenografts; similar results were observed using siRNA nanocapsule-mediated PARN targeting. Pharmacological targeting of STAT3 also confirmed PARN regulation by STAT3 signaling. In sum, these results suggest that a STAT3-PARN regulatory network plays a pivotal role in tumor progression and thus may represent a target for glioblastoma therapeutics. SIGNIFICANCE: A positive feedback loop comprising PARN and EGFR-STAT3 signaling supports self-renewal and proliferation of glioblastoma stem cells to drive tumor progression and can be targeted in glioblastoma therapeutics.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/patologia , Neoplasias Encefálicas/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proliferação de Células , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
There is emerging evidence for the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with mCRPC with patients harboring germline or somatic mutations deriving clinical benefit. However, the toxicity profile of PARPi in mCRPC is not well established. In March 2022 a literature search was conducted across 4 databases - Medline, PubMed, Cochrane Library and Embase. In total, 14 relevant studies were identified cumulating in 2066 patients that were treated with PARPi. The overall ORR to PARPi alone or in combination with other therapy was 37% (246/666). In 5trials that investigated PARPi alone, the ORR was 39% (141/361). Treatment emergent adverse events (TEAEs) of any grade were reported in 96% (1034/1080) in PARPi treatment arms. TEAEs of grade >= 3 were reported in 57% (611/1080). 45% (457/1006) experienced treatment interruption whilst 31% (310/989) required dose reductions. 11% (114/1006) of patients had their treatment discontinued directly as the result of toxicity associated with the trial medications. The most common hematological toxicity was anemia, reported in 490/1160 (42%) patients. and lowered white blood cell count were the next 2most common toxicities, reported in 186/655 (28%) and 133/729 (18%) respectively. The 3most common non-hematological toxicities reported were nausea, fatigue and anorexia reported in 440/1013 (43%), 340/1013 (34%) and 274/1013 (27%) patients respectively. Overall, TRAEs associated with individual PARPi are still emerging with hematological toxicities being most apparent. Further toxicities will be informed from future clinical trials to allow improved treatment selection, education and management of toxicities in prostate cancer.
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Anemia , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Anemia/induzido quimicamente , Seleção de Pacientes , Ftalazinas/efeitos adversosRESUMO
Immune checkpoint inhibitors have been incorporated into the treatment of various malignancies. An increasing body of literature is reporting rare but potentially fatal adverse events associated with these agents. In this case series, the authors report the clinical features and outcomes of seven patients who received immune checkpoint inhibitors for different solid organ malignancies and developed a tetrad of immune-related myocarditis, myositis, myasthenia gravis and transaminitis. Herein the authors review the literature and describe the current diagnostic and management approach for this overlapping syndrome. The authors' series highlights the importance of a high index of clinical suspicion, prompt comprehensive investigations, early multidisciplinary team involvement and initiation of immunosuppressive therapy when immune-related adverse events are suspected.
Cancer immunotherapy is used in the treatment of different cancer types. Immunotherapy activates the immune system to detect and attack cancer cells, but side effects may arise from the immune system inadvertently attacking normal tissues and organs. The increased use of immunotherapy has led to an increase in the reporting of rare but potentially life-threatening treatment-related side effects. In this case series, the authors report the clinical features and outcomes of seven patients who developed inflammation of the heart, muscles, nerve and muscle junctions and liver following treatment with immunotherapy. The authors review the scientific literature and discuss the current understanding of and management approach to this rare syndrome. The authors' report highlights the importance of a high degree of clinical suspicion, prompt comprehensive testing to confirm diagnosis, early involvement of experts from different specialties and early initiation of treatment in the management of this unique syndrome.
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Miastenia Gravis , Miocardite , Miosite , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Miastenia Gravis/induzido quimicamente , Miocardite/induzido quimicamente , Miocardite/diagnóstico , Miocardite/tratamento farmacológico , Miosite/induzido quimicamente , Miosite/diagnóstico , Neoplasias/tratamento farmacológicoRESUMO
Prostate adenocarcinoma with testicular metastasis is rare, present in up to 4% of autopsy diagnoses, and presents symptomatically in less than 0.5% of cases. We report an unusual case of a 55-year-old male who developed a symptomatic testicular metastasis from primary prostate cancer 4 years after initial diagnosis of metastatic castrate-sensitive prostate cancer with nodal and bone-only involvement. The patient had orchidectomy, histologically confirming the metastasis and revealing sparing of the spermatic cord. Prior treatment for his metastatic castrate-sensitive prostate cancer had included androgen deprivation therapy and upfront docetaxel chemotherapy. He had received palliative radiotherapy for symptomatic bone metastasis and managed on enzalutamide for castrate-resistant disease for the preceding 22 months with ongoing PSA response at the time of diagnosis of new testicular metastasis, with a further significant PSA response following his "testicular metastasectomy." At the time of diagnosis of testicular metastasis, he did not have any evidence of other visceral metastases, and his metastatic disease otherwise remained radiologically stable. We describe his disease course, treatment and outline the rare nature of his case of testicular metastasis from prostate cancer.
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INTRODUCTION: Recently, electric cigarettes with liquid (e-liquid) were introduced as an alternative to tobacco smoking. They were promoted as possible cessation aids and were considered to be potentially less harmful than traditional tobacco-based cigarettes. However, there is little information on the toxicants present in e-liquids and their possible carcinogenic effects. METHODS: Western blot analysis was performed to identify the protein levels of cancer progression related signal transducers. Patient-derived brain tumor cells (CSC2) were injected into mouse brains and tumor growth was then observed by performing magnetic resonance imaging (MRI) and hematoxylin and eosin (H&E) staining of the whole brain. Immunohistochemistry (IHC) staining and Immunofluorescence staining were performed to study the expression of pEGFR and pERK. RESULTS: Western blotting revealed that e-liquids increased pEGFR and pERK expression in a dose dependent manner. Animal experiments revealed that the e-liquid treated group had accelerated tumor growth and poor prognosis compared to the vehicle group. Histological staining showed activation of pEGFR and pERK in the e-liquid treated group. CONCLUSION: Our study revealed that e-liquid activates pEGFR and pERK, leading to accelerated brain tumor growth and poor prognosis.
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Neoplasias Encefálicas/metabolismo , Carcinogênese/efeitos dos fármacos , Sistemas Eletrônicos de Liberação de Nicotina , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glioblastoma/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nicotina/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fumar Cigarros/metabolismo , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Feminino , Glioblastoma/patologia , Xenoenxertos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias/métodos , Fosforilação/efeitos dos fármacos , Prognóstico , Propilenoglicol/administração & dosagem , Soluções , Solventes/administração & dosagem , Carga Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Oral metastasis by hepatocellular carcinoma (OMHCC) is extremely rare, and the prognosis had been reported quite poor due to simultaneous multiple organ metastases. In this study, we report clinical features and survival of 10 new cases of OMHCC and suggest the criteria for palliative surgery. METHODS: A retrospective clinical study including 10 new cases of oral OMHCC between 2006 and 2016 was performed. Clinical features and survival analysis were examined. The recorded variables were age, sex, site of oral metastases, size of oral tumor (largest diameter), and survival after oral histopathologic diagnosis. RESULTS: There was male (n=8) predilection of OMHCC. The mean survival time was 16.9 months. Patient age ranged from 40 to 71 years (mean 56.5). Eight mandibular and two maxillary lesions were found. One patient showed simultaneously the maxilla and the oral tongue involvement. The most often encountered symptoms were swelling (80%) followed by pain (60%), numbness (60%), bleeding (10%), and tooth mobility (10%). Four patients underwent operation due to spontaneous bleeding and swelling of the cancer. Overall (from onset of hepatocellular carcinoma) and truncated survival (from onset of OMHCC) were 71.9 and 13.1 months respectively. CONCLUSION: The prognosis of OMHCC was quite poor. Oral and jaw bone examination should be included in patients with multiple metastasis of HCC. Palliative surgery might be performed in patients who reported spontaneous bleeding, severe pain, and oral dysphasia due to tumor enlargement.
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As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Bainha de Mielina/metabolismo , Receptor Nogo 1/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 1 Inibidora de Diferenciação/metabolismo , Proteínas Inibidoras de Diferenciação/metabolismo , Camundongos Endogâmicos BALB C , Bainha de Mielina/patologia , Proteases Específicas de Ubiquitina/metabolismoRESUMO
The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.
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Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Monoacilglicerol Lipases/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Células Cultivadas , Feminino , Glioblastoma/genética , Glioblastoma/terapia , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Ativação de Macrófagos/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Monoacilglicerol Lipases/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/genética , Interferência de RNA , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
BACKGROUND: The purpose of this study is to introduce our modified disc plication technique using MITEK mini anchors and to evaluate the clinical outcome for patients with internal derangement (ID) of the temporomandibular joint (TMJ). PATIENTS AND METHODS: We evaluated 65 joints in 46 patients, comprised 32 women and 14 men, who first visited the Asan Medical Center from December 2012 to December 2016. The age of the patients ranged from 14 to 79 years, with a mean age of 36.6 years. The patients presented with joint problems including pain, joint noise, and mouth opening limitation (MOL). Patients who met our inclusion criteria underwent unilateral or bilateral disc repositioning surgery with our minimally invasive disc plication technique using MITEK mini anchors and No. 2-0 Ethibond® braided polyester sutures. The variables taken into account in this study were the range of maximum mouth opening (MMO), painful symptoms (evaluated with the visual analog scale, VAS), and the type of noise (click, popping, crepitus) in the TMJ. RESULTS: Preoperative examination revealed painful symptoms in 50.7% (n = 35) of the operated joints (n = 69) and the presence of clicks in 56.5% (n = 39). Postoperative examination revealed that 4.3% (n = 3) of the operated joints had painful symptoms with lower intensity than that in the preoperative condition. Additionally, 17.4% (n = 12) had residual noise in the TMJ, among which two were clicking and the other 10 had mild crepitus. The intensity of the postoperative residual noise was significantly decreased in all cases compared to that in the preoperative condition. Among patients with MOL below 38 mm (n = 18), the mean MMO was 31.4 mm preoperatively and 44.2 mm at 6 months postoperatively, with a mean increase of 13.8 mm. A barely visible scar at the operation site was noted during the postoperative observation period, with no significant complications such as facial palsy or permanent occlusal disharmony. CONCLUSION: Subjective symptoms in all patients improved following the surgery. TMJ disc plication using MITEK mini anchors with our minimally invasive approach may be a feasible and effective surgical option for treating TMJ ID patients who are not responsive to conservative treatment.
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The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity.
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Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Linhagem Celular Tumoral , Células HeLa , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Purinas/metabolismoRESUMO
Background: Recent trials of novel agents in 'rare' molecular subtypes of non-small cell lung cancer (NSCLC) have used single-arm trial designs and benchmarked outcomes against historical controls. We assessed the consistency of historical control outcomes using docetaxel data from published NSCLC randomized controlled trials (RCTs).Material and methods: Advanced NSCLC RCTs including a docetaxel monotherapy arm were included. Heterogeneity in tumor objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS), and correlations between outcomes and year of trial commencement were assessed.Results: Among 63 trials (N = 10,633) conducted between 2000 and 2017, ORR ranged from 0% to 26% (I2 = 76.1%, pheterogeneity < .0001). Mean of the median PFS was 3.0 months (range: 1.4-6.4), 3-month PFS ranged from 25% to 85% (I2 = 86.0%, pheterogeneity < .0001). Mean of the median OS was 9.1 months (range: 4.7-22.9), 9-month OS ranged from 23% to 79% (I2 = 83.0%, pheterogeneity < .0001). Each later year of trial commencement was associated with 0.3% (p = .046), 0.5% (p = .11) and 0.9% (p = .001) improvement in ORR, 3-month PFS and 9-month OS rates, respectively.Conclusions: There was significant heterogeneity and an improving trend in docetaxel outcomes across trials conducted over 20 years. Benchmarking biomarker-targeted agents against historical controls may not be a valid approach to replace RCTs. Innovative study designs involving a concurrent control arm should be considered.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Benchmarking , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Docetaxel/administração & dosagem , Feminino , Estudo Historicamente Controlado , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Metanálise como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Glioblastoma (GBM) cancer stem cells (CSC) are primarily responsible for metastatic dissemination, resistance to therapy, and relapse of GBM, the most common and aggressive brain tumor. Development and maintenance of CSCs require orchestrated metabolic rewiring and metabolic adaptation to a changing microenvironment. Here, we show that cooperative interplay between the mitochondrial chaperone TRAP1 and the major mitochondria deacetylase sirtuin-3 (SIRT3) in glioma stem cells (GSC) increases mitochondrial respiratory capacity and reduces production of reactive oxygen species. This metabolic regulation endowed GSCs with metabolic plasticity, facilitated adaptation to stress (particularly reduced nutrient supply), and maintained "stemness." Inactivation of TRAP1 or SIRT3 compromised their interdependent regulatory mechanisms, leading to metabolic alterations, loss of stemness, and suppression of tumor formation by GSC in vivo. Thus, targeting the metabolic mechanisms regulating interplay between TRAP1 and SIRT3 may provide a novel therapeutic option for intractable patients with GBM. SIGNIFICANCE: Discovery and functional analysis of a TRAP1-SIRT3 complex in glioma stem cells identify potential target proteins for glioblastoma treatment.
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Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Células-Tronco Neoplásicas/patologia , Estresse Oxidativo , Sirtuína 3/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Feminino , Glioblastoma/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismoRESUMO
Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPß, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPß expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. ©2017 AACR.
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Neoplasias Encefálicas/patologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteínas de Ligação ao GTP/antagonistas & inibidores , Glioma/patologia , Células-Tronco Mesenquimais/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Transglutaminases/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Transdiferenciação Celular , Feminino , Proteínas de Ligação ao GTP/metabolismo , Glioma/genética , Glioma/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteína 2 Glutamina gama-Glutamiltransferase , Transglutaminases/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
[This corrects the article DOI: 10.1371/journal.pbio.1002152.].
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Upregulation of microRNA-21 (miR-21) is known to be strongly associated with the proliferation, invasion, and radio-resistance of glioma cells. However, the regulatory mechanism that governs the biogenesis of miR-21 in glioma is still unclear. Here, we demonstrate that the DEAD-box RNA helicase, DDX23, promotes miR-21 biogenesis at the post-transcriptional level. The expression of DDX23 was enhanced in glioma tissues compared to normal brain, and expression level of DDX23 was highly associated with poor survival of glioma patients. Specific knockdown of DDX23 expression suppressed glioma cell proliferation and invasion in vitro and in vivo, which is similar to the function of miR-21. We found that DDX23 increased the level of miR-21 by promoting primary-to-precursor processing of miR-21 through an interaction with the Drosha microprocessor. Mutagenesis experiments critically demonstrated that the helicase activity of DDX23 was essential for the processing (cropping) of miR-21, and we further found that ivermectin, a RNA helicase inhibitor, decreased miR-21 levels by potentially inhibiting DDX23 activity and blocked invasion and cell proliferation. Moreover, treatment of ivermectin decreased glioma growth in mouse xenografts. Taken together, these results suggest that DDX23 plays an essential role in glioma progression, and might thus be a potential novel target for the therapeutic treatment of glioma.
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Neoplasias Encefálicas/metabolismo , RNA Helicases DEAD-box/metabolismo , Glioma/metabolismo , MicroRNAs/biossíntese , Animais , Antiparasitários/farmacologia , Neoplasias Encefálicas/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , RNA Helicases DEAD-box/genética , Bases de Dados Factuais/estatística & dados numéricos , Glioma/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imunoprecipitação , Marcação In Situ das Extremidades Cortadas , Ivermectina/farmacologia , Camundongos , MicroRNAs/genética , RNA Interferente Pequeno/farmacologia , Transdução Genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.
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Receptores ErbB/metabolismo , Proteínas do Olho/metabolismo , Glioma/etiologia , Células-Tronco Neoplásicas/metabolismo , Fatores de Crescimento Neural/metabolismo , Serpinas/metabolismo , Animais , Comunicação Autócrina , Progressão da Doença , Feminino , Glioma/metabolismo , Glioma/mortalidade , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/metabolismo , Receptores Notch/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição STAT3/metabolismoAssuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Vasos Coronários/patologia , Macrófagos/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Neovascularização Patológica/metabolismo , Animais , Vasos Coronários/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Imuno-Histoquímica , Masculino , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Synthesis of a new series of diarylureas and diarylamides possessing 4-aryl-8-amino(acetamido)quinoline scaffold is described. Their in vitro antiproliferative activities against ten melanoma cell lines were tested. Compounds 1l, 2l, 3c, and 4c showed the highest potency against A375P cell line with IC50 values in sub-micromolar scale. Compound 4c was equipotent to Vemurafenib against A375P. In addition, compounds 1l, 2a, and 2l showed high potency over the NCI-9 tested melanoma cell line panel. The IC50 values of compounds 1l and 2l were in 2-digit nanomolar scale over four and five cell lines, respectively. Compound 2l showed high, dose-dependent inhibition of ERK kinase. ADME profiling showed that compounds 1l, 2l, 3c, 4c, and 5b are estimated to be orally bioavailable.
Assuntos
Acetamidas/farmacologia , Amidas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Ureia/química , Acetamidas/síntese química , Acetamidas/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Melanoma/enzimologia , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Ureia/análogos & derivadosRESUMO
Synthesis of a new series of 3,4-diarylpyrazole-1-carboxamide derivatives is described. Their antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The biological results indicated that five synthesized compounds (Ig, Ii, IIc, IIg, and IIh) exhibited similar activity to Sorafenib. In addition, three compounds (IIa, IIb, and IIi) were more potent than Sorafenib. Among all of these derivatives, compound IIa which has dimethylamino and phenolic moieties showed the most potent antiproliferative activity against A375P human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIa into the domain of V600E-b-Raf and the binding mode was studied.